Medulloblastoma (MB) is the most common malignant brain tumor that develops in the cerebellum. MB occurs mostly in children between the ages of 3-7 years. Human MBs are classified into four major subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which has distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs represent the most aggressive subgroups and the least responsive to current therapeutic regimen. Extensive molecular analysis of human MBs identified large chromosomal copy number changes and few, recurrent oncogenic point mutations, mainly in epigenetic regulators, that might be targeted therapeutically.
Over the years we have developed mouse models of WNT, SHH and G3 tumors that recapitulate their human counterparts, in addition to patient-derived orthotopic xenografts (PDOX) of the four subgroups. These models are currently used to evaluate several FDA approved compounds that markedly reduced the proliferation of the most aggressive SHH and G3 MBs in vitro via a preclinical drug development pipeline. After detailed intracranial PK and PD studies confirming blood brain penetration, drugs are evaluated as single agents and in rational combinations in tumor-bearing animals.
Our studies provide a comprehensive and integrated platform in which molecular analysis drives identification of FDA-approved drugs and preclinical trials with mouse and human medulloblastoma to identify the best candidate drugs to be translated into the clinic.